Growth hormone (GH), released by the pituitary, is a member of a cascade of hormones that regulate growth of the body and its organs. Secretion of GH into the bloodstream is followed by binding to growth hormone receptor (GHR) on many cell and organ types. Growth hormone signaling is mediated by this interaction. Growth hormone signaling causes the production of another hormone, insulin-like growth factor I (IGF-I), which is produced in the liver, adipose tissue, kidney and other organs and secreted into the bloodstream. About 75% of serum IGF-I is produced in the liver in response to GH stimulation. Many disorders are caused by and/or associated with increased GH levels and/or increased IGF-I levels in plasma and/or tissues including acromegaly, gigantism, retinopathy, macular degeneration, nephropathy, diabetes and cancers. The role of GH and IGF-I in these and other disorders is well recognized. The role of IGF-I in mediating many GH effects is well recognized and this interrelationship is referred to as the GH/IGF-I axis. In a normal feedback loop, IGF-I also causes the production of GH by the pituitary to be reduced. There is a need for treatments that reduce IGF-I levels in a subject, for example, more effectively, safely, conveniently and/or at reduced cost.
Somavert, a GH variant having antagonistic activity is approved in the treatment of acromegaly for its ability to reduce serum IGF-I levels in a patient. For a review of current practices for the treatment of acromegaly see Guistina et al., 2011. Briefly, in acromegaly, surgery is first used in treatment to debulk the tumor and reduce the pituitary tumor's GH secretion and reduce production of IGF-I in the serum. Medicinal treatments are also used to reduce serum IGF-I and in some cases also reduce GH release. All treatments use a medicinal monotherapy or a combination therapy where the combination is directed to two different biological targets. First line medicinal treatment is with a somatostatin (SST) agonist, and this treatment is started initially at low doses and escalated to doses that reduce GH and normalize the patients serum IGF-I. When an SST agonist treatment fails, a dopamine agonist is used in combination with a SST agonist, or Somavert is used in combination with a SST agonist or Somavert is used as a monotherapy. Somavert doses typically start with a loading dose of 40 mg on the first day, and 10 mg daily doses, and these daily doses are escalated until normalization of serum IGF-I, with up to 30 mg daily doses approved. There are failures with the highest approved daily doses of Somavert, and clinicians have escalated beyond approved doses. Somavert is however, prohibitively expensive, requires inconvenient daily (once or twice daily) injection, is a lyophilized powder and needs reconstitution, has safety issues causing injection site reactions and an increase in liver enzymes, and produces undesirable increases in GH. Thus, clinicians typically do not seek to use Somavert in different combination therapies to those outlined above. In patients where first line therapy using SST has failed or in patients where Somavert monotherapy or combination with SST has failed, clinicians are seeking new more effective monotherapies. Combination therapies using, for example, Somavert are only considered with a drug directed to a different biological target and typically an SST agonist, as SST agonists have potential to reduce tumor size.